Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][CH:24]([F:38])[O:25][C:26]1[CH:27]=[C:28]([S:34]([Cl:37])(=[O:36])=[O:35])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[ClH:37].[F:38][CH:24]([F:23])[O:25][C:26]1[CH:27]=[C:28]([S:34]([NH:20][C:18]2[CH:17]=[CH:16][C:15]([O:21][CH3:22])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)(=[O:36])=[O:35])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC(F)F
Product: COc1ccc(S(=O)(=O)Nc2ccc(OC)c(N3CCNCC3)c2)cc1OC(F)F
Product: Cl

Procedure:
The compound was prepared as described for Example 1 by reaction of 4-(5-amino-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and commercially available 3-difluoromethoxy-4-methoxy benzene sulfonylchloride, followed by deprotection under acidic conditions.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.[C:28]([O:32][C:33]([N:35]1[CH2:39][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=2)[CH:37]([C:48](O)=[O:49])[CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[Cl:47][C:42]1[CH:41]=[C:40]([CH:38]2[CH:37]([C:48]([N:25]3[CH2:26][CH2:27][N:22]([C:20]4[C:21]5[C@H:13]([CH3:12])[CH2:14][CH2:15][C:16]=5[N:17]=[CH:18][N:19]=4)[CH2:23][CH2:24]3)=[O:49])[CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:39]2)[CH:45]=[CH:44][C:43]=1[Cl:46]
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4CN(C(=O)OC(C)(C)C)CC4c4ccc(Cl)c(Cl)c4)CC3)c21
Reaction time: 2 h

Procedure:
DIPEA (35.5 mg, 0.275 mmol) was added to a suspension of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (20 mg, 0.069 mmol), 1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (29.7 mg, 0.082 mmol), and O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31.3 mg, 0.082 mmol) in CH2Cl2 (5 mL) at room temperature. The resulting mixture was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NH4Cl. The organic layer was dried (MgSO4) and concentrated. The residue was purified by a silica cartridge (5.0 g), eluted by a mixture of EtOAc and hexanes (60:40) to give the tert-butyl 3-(3,4-dichlorophenyl)-4-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)pyrrolidine-1-carboxylate as a mixture of diastereomers (34 mg, 88%). LCMS (APCI+) [M-Boc+H]+ 560.0; Rt: 3.59 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[O:11]=[CH:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (90 mL, 1.03 mol) in CH2Cl2 was added dropwise a solution of DMSO (100 mL, 1.41 mol) in CH2Cl2. The mixture was stirred at −78° C. for 1 hr, and a solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (90 g, 0.51 mol) in CH2Cl2 was added. After stirring for 3 hr, 500 mL of triethylamine was added and the reaction mixture was stirred for another 3 h at −78° C. The reaction was quenched with 1% HCl and the reaction mixture was warmed to RT. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The organic layer was washed with water, dried over MgSO4, and evaporated to provide crude N.1, (R)-tert-butyl 1-oxopropan-2-ylcarbamate (76.0 g, 85.4%). 1H NMR (CDCl3) δ 9.56 (s, 1H), 4.23 (br s, 1H), 1.45 (s, 9H), 1.32 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27.7 %

Procedure:
4-Amino-1-N-Boc piperidine (1.80 g, 8.9 mmol) was dissolved in CH2Cl2 and 4-chlorobenzylbromide (1.84g, 8.9 mmol) and triethylamine (1.25 mL, 8.9 mmol) were added. The solution was allowed to stir for 14 h at room temperature and evaporated in vacuo and partitioned between ether/1N NaOH. The aqueous layer was removed and the ether was washed with brine and dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride) to yield the title compound (0.800 g, 27%). 1H-NMR (CDCl3): δ 1.26 (m, 1H), 1.44 (s, 9H), 1.83 (d, 2H), 2.63 (t, 1H), 2.78 (t, 2H), 3.46 (s, 2H), 3.78 (s, 2H), 4.00 (bs, 2H), 7.26 (bs, 4H). ESI-MS m/z: 325.1 (M+1), retention time 1.86.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:25]=1)#[N:2].Cl[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:10]1([CH3:13])[CH2:9][CH:8]([N:14]2[CH2:15][CH2:16][N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:27]2=[O:28])[C:7]2[CH:25]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC(NCCNCc2ccccc2)c2cc(C#N)ccc2O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(N2CCN(Cc3ccccc3)C2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4-yl)-N'-benzylethylenediamine (0.91 g, 2.71 mmole, from Example 22, part A) and 4-nitrophenyl chloroformate (0.57 g, 2.85 mmole) in methylene chloride (22.5 ml) cooled to 0° C. was added pyridine (0.27 g, 3.39 mmole). The reaction mixture was stirred at room temperature for 24 hours, diluted with methylene chloride and washed with 5% aqueous HCl solution, 2N NaOH solution and saturated NaCl solution. The extract was dried over MgSO4 and evaporated in vacuo to obtain 1.32 g of an orange gum. The crude product was chromatographed on silica eluting with hexane/ethyl acetate (3:2) to obtain 0.65 g (66%) of the title compound as a colorless amorphous solid, m.p.=45-48° C. 1H NMR (CDCl3) δ 7.51-7.39 (m, 7H), 6.93 (d, J=9.38 Hz, 1H), 5.43 (dd, J=7.03 and 11.14 Hz, 1H), 4.55 (m, 2H), 3.36-3.20 (m, 3H), 3.05 (m, 1H), 1.99 (m, 2H), 1.59 (s, 3H), 1.45 (S, 3H); 13C NMR (CDCl3) δ 160.77, 158.29, 136.70, 132.49, 131.66, 128.60, 128.03, 127.48, 121.38, 119.16, 118.61, 103.29, 76.94, 48.17, 45.15, 41.90, 37.26, 34.96, 34.67, 29.75, 24.01; MS: (M+H)+ @362.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[Si:13]([O:1][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OCCC1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3-hydroxydihydrofuran-2(3H)-one (5 g, 49 mmol) in anhydrous DMF (50 mL) was added imidazole (6.7 g, 98 mmol) and TBDMS chloride (8.1 g, 54 mmol). The reaction was allowed to stir under an N2 atmosphere at room temperature overnight. The reaction was diluted with diethyl ether and washed with 1 N aqueous HCl×2 then brine×1. The organic phase was dried over Na2SO4 and the solvent removed in vacuo to yield 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) as a clear oil. [M+H] calc'd for C10H20O3Si, 217. found, 217.
Reaction SMILES: [NH:1]([C:3]1[S:7][CH:6]=[N:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH2:2].O=[C:14]([CH3:29])[CH:15]([C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CO>[CH3:20][O:19][C:17](=[O:18])[CH2:16][C:15]1[C:14]([CH3:29])=[N:2][N:1]([C:3]2[S:7][CH:6]=[N:5][C:4]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:21]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccn1
Reactant: CCOC(=O)c1ncsc1NN
Solvent: CO
Product: CCOC(=O)c1ncsc1-n1nc(C)c(CC(=O)OC)c1-c1ccccn1
Temperature: 90 °C
Yield: 68.8 %

Procedure:
In a microwave reactor, 0.358 g (1.91 mmol) of ethyl 5-hydrazinyl-1,3-thiazole-4-carboxylate were added to 0.450 g (1.91 mmol) of methyl 4-oxo-3-(pyridin-2-ylcarbonyl)pentanoate in 4 ml methanol. In a microwave oven the closed vessel was heated at 90° C. for 2 hours. After removal of the solvent, the residue was extracted repeatedly with dichloromethane/water. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography of the residue gave 0.508 g of product (61.8% of theory), NMR (CDCl3, 300 MHz): 1.12 (t, 3H); 2.35 (s, 3H); 3.66 (s, 2H); 3.69 (s, 3H); 4.08 (s, 3H); 7.19 (m, 1H); 7.32 (m, 1H); 7.66 (m, 1H); 8.51 (m, 1H); 8.72 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([O:9]/[C:10](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:42])[C:30]([O:32]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:24]=2)=[CH:19][CH:18]=1)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:8].O.C(OCC)(=O)C>CN(C)C=O>[CH2:7]([O:9]/[C:10](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:42])[C:30]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:32])[N:24]=2)=[CH:19][CH:18]=1)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:8]
Reactant: CCCCCN
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)OCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
0.21 mL (1.8 mmol) of n-pentylamine is added to a solution of 0.45 g (0.9 mmol) of ethyl (Z)-2-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)acrylate (prepared according to Example 2d) in 15 mL of dimethylformamide. The tube is sealed and rapidly placed in an oil bath preheated to 80° C. The reaction mixture is stirred at 80° C. for 1 hour 30 minutes. After cooling, the reaction is worked up by addition of 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture to give 0.2 g (57%) of ethyl (Z)-2-ethoxy-3-{4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}acrylate in the form of a pale yellow solid.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].O[N:6]=[C:7]([NH2:20])[CH2:8][C:9]1[C:18]([Br:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:19][C:18]1[C:9]([CH2:8][C:7]2[NH:20][S:1][O:2][N:6]=2)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: NC(Cc1cc2ccccc2cc1Br)=NO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Brc1cc2ccccc2cc1CC1=NOSN1
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
Thionyl chloride (2.0M/CH2Cl2 ; 7.4 mL, 0.015 mol) was added dropwise to a stirred suspension of N'-hydroxy-(3-bromo-2-naphthalenyl)ethanimidamide (3.29 g, 0.012 mol), methylene chloride (125 mL) and pyridine (2.4 mL, 0.03 mol) at 5° C. After 20 minutes at -5° C., the reaction solution was added to ice/H2O. The organic layer was separated, washed with saturated NaCl, dried over MgSO4 and concentrated in vacuo to a slurry (20 mL). Diethyl ether (20 mL) was added and the title compound (1.40 g, yield 36%) was collected (153°-154° C. decomp.).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([CH:11]1[CH2:16][S:15][CH2:14][CH2:13][N:12]1[C:17]([O:19]C(C)(C)C)=O)=[O:10])C(OC)=O.C(O)(C(F)(F)F)=O>ClCCl>[OH:1][CH2:2][C@H:3]1[C:17](=[O:19])[N:12]2[CH:11]([CH2:16][S:15][CH2:14][CH2:13]2)[C:9](=[O:10])[NH:8]1
Reactant: COC(=O)[C@H](CO)NC(=O)C1CSCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@@H](CO)C(=O)N2CCSCC12
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
To a solution of the crude 1,1-dimethylethyl 3-({[(1S)-1-(hydroxymethyl)-2-(methyloxy)-2-oxoethyl]amino}carbonyl)-4-thiomorpholinecarboxylate (D118, 3.87 g) in 44 ml of dichloromethane were added under N2, at r.t., 22 ml of TFA. The reaction mixture was stirred at room temperature for 3 hrs. The solvents were removed under reduced pressure and the residue was purified on a SCX cartridge. The fraction eluted with 2M methanolic ammonia was evaporated to dryness and the residue was dissolved in MeOH and refluxed for 20 hrs. The reaction mixture was evaporated to dryness and the desired product was purified by SCX, eluting with MeOH. The title compound (1.1 g, y=92% over 2 steps) was isolated as a mixture of diastereoisomers (ratio ˜50/50).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([O:33][CH3:32])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C(=O)O)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 85 mg (0.561 mmol) of 3-methoxybenzoic acid, 143 mg (0.561 retool) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.45, FD-MS: M+ =561.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][C:20](=[O:26])[CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21[O:14][CH2:13][CH2:12][O:11]2.S(=O)(=O)(O)[OH:28].C(OCC)C.O>CN(C)C=O.[O-2].[O-2].[O-2].[Cr+6]>[O:26]=[C:20]([CH2:21][O:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][CH:17]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:28])=[O:1]
Reactant: CCCOCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCC(=O)O
Reaction time: 1 h

Procedure:
Chromium trioxide (9.8 g.) (dried over phosphorus pentoxide) was added portionwise with stirring to a solution of 6-(7-hydroxyhepty)-7-(3-oxo-4-propoxybut-1-enyl)-1,4-dioxaspiro[4,4]nonane (8.6 g.) in dry dimethylformamide (130 ml.) at a temperature lower than 0° C. Concentrated sulphuric acid (3.5 ml.) in dimethylformamide (130 ml.) was added and the mixture stirred at below 10° C. for 1 hour. Diethyl ether was added followed by a minimum quantity of water to produce two readily separable layers. The ether layer was separated and stirred with aqueous 2 N sodium carbonate solution. The aqueous layer was separated, washed with diethyl ether and then covered with a layer of diethyl ether and acidified to pH 5 by the addition of 20% aqueous sodium dihydrogen phosphate solution. The ethereal layer was separated and the aqueous layer again extracted with diethyl ether. The combined ethereal layers were dried over sodium sulphate and evaporated to give 7-{7-(3-oxo-4-propoxybut-1-enyl)-1,4-dioxaspiro[ 4,4]-non-6-yl}heptanoic acid (2.1 g.),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[O:13].[CH:21]1[CH2:25][CH:24]=[CH:23][CH:22]=1>C(#N)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[CH:24]3[CH2:25][CH:21]=[CH:22][CH:23]3[C:16]3[CH:15]=[C:14]([C:12](=[O:13])[CH3:11])[CH:19]=[CH:18][C:17]=3[NH:20]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C1=CCC=C1
Reactant: CC(=O)c1ccc(N)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: COc1ccc(C2Nc3ccc(C(C)=O)cc3C3C=CCC32)cc1
Temperature: 25 °C
Reaction time: 2.3 h
Yield: 75.1 %

Procedure:
4-Methoxybenzaldehyde (0.074 g, 0.5 mmol) and 4-aminoacetophenone (0.068 g 0.5 mmol) were heated to melting in a round bottom flask, then a solution of the catalyst Sc(OTf)3 (0.0248 g, 0.05 mmol, 10 mol %) in anhydrous acetonitrile (0.2 mL) was added to the molten solid, followed by a solution of cyclopentadiene (0.165 g, 2.5 mmol) in acetonitrile (3 mL). The reaction was stirred at rt for 2.30 h. The reaction mixture was concentrated under reduced pressure. The crude material was purified by preparative column chromatography using silica gel (SiO2) eluted with 10% EtOAc/Hexanes to give the product as a colorless solid (0.120 g, 76%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:41](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:41])[CH2:35][CH2:34]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(-c3ccc(N4CCNCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.2 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(4-piperazin-1-ylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (89 mg, 0.18 mmol) in dichloromethane (3 mL) was added formaldehyde (37% in water) (80 μL, 1.06 mmol) and sodium triacetoxyborohydride (113 mg, 0.53 mmol). The reaction was stirred (rt) for 17 h. The mixture was diluted with dichloromethane (25 mL) and was washed with H2O (1×20 mL), brine, and was dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC using a gradient elution from 5% to 30% acetonitrile in water to obtain 53 mg (58%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.99-7.91 (m, 3 H), 7.86-7.79 (m, 1 H), 7.69-7.63 (m, 1 H), 7.39-7.26 (m, 5 H), 7.23-7.17 (m, 1 H), 7.06-6.98 (m, 3 H), 5.66 (s, 2 H), 3.27-3.14 (m, 4 H), 2.47-2.40 (m, 4 H), 2.22 (s, 3 H); ES-MS m/z 515.32 [M+H]+, HPLC RT (min) 2.36.
Reaction SMILES: Cl.[CH2:2]([O:4][C@H:5]1[CH2:9][NH:8][C@H:7]([C:10]([OH:12])=[O:11])[CH2:6]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[C:19](=O)([O:35]N1C(=O)CCC1=O)[O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>O1CCOCC1.O>[CH:33]1[C:34]2[CH:22]([CH2:21][O:20][C:19]([N:8]3[CH2:9][C@H:5]([O:4][CH2:2][CH3:3])[CH2:6][C@H:7]3[C:10]([OH:12])=[O:11])=[O:35])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CCO[C@H]1CN[C@H](C(=O)O)C1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.9 %

Procedure:
(2S,4R)-4-Ethoxypyrrolidine-2-carboxylic acid hydrochloride (Compound SP820) (45 g, 230 mmol) was dissolved in a mixture of 1,4-dioxane (500 ml) and water (500 ml), potassium carbonate (79.4 g, 574 mmol) and (9H-fluoren-9-yl)methyl (2,5-dioxopyrrolidin-1-yl) carbonate (Fmoc-OSu, 69.8 g, 207 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with diethyl ether, and the aqueous layer was adjusted to pH 3 with an aqueous potassium bisulfate solution and extracted with ethyl acetate. The resulting organic extract was washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to afford (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-ethoxypyrrolidine-2-carboxylic acid (Compound SP813, Fmoc-Hyp(Et)-OH) (90.7 g, 103%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[N:6][CH:7]=1.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[CH:21])[CH3:17].C(N(CC)CC)C>C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[C:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[N:6][CH:7]=1)[CH3:17]
Reactant: C#CC(OCC)OCC
Reactant: Fc1ccc(-c2ccc(Br)cn2)cc1F
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(C#Cc1ccc(-c2ccc(F)c(F)c2)nc1)OCC
Reaction time: 2 h

Procedure:
A mixture of 2.00 g of crude 5-bromo-2-(3,4-difluorophenyl)pyridine (GC purity 81%), 1.12 ml of 3,3-diethoxy-1-propine, 0.138 g of tetrakis(triphenylphosphine)palladium, 0.052 g of copper(I) bromide and 36 ml of triethylamine was heated to boiling for 2 hours. After cooling the reaction mixture was diluted with 100 ml of diethyl ether, washed twice with 40 ml of water each time, dried over sodium sulphate, filtered, the filtrate was boiled briefly with active charcoal, filtered and concentrated. The crude 5-(3,3-diethoxy-1-propynyl)-2-(3,4-difluorophenyl)pyridine, (2.58 g; GC purity 72%), obtained as a brown-black oil, was used directly in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[Na+].[Cl-]>O1CCOCC1.C(Cl)(Cl)Cl>[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 88.4 %

Procedure:
N-(3-Bromopropyl)phthalimide (16.7 g, 62.4 mmol) is added to a stirred solution of 1-isopropyl-piperazine (8.00 g, 62.4 mmol) and diisopropylethylamine (8.06 g, 62.4 mmol) in anhydrous 1,4-dioxane (300 mL). The resultant mixture is heated in an oil bath at 90° C. for 20 hours. At ambient temperature, chloroform (300 mL) and half-saturated aqueous NaCl (200 mL) are added to the mixture. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated. The crude oil is subjected to chromatography on silica gel and eluted with 2 M NH3/CH3OH in dichloromethane 0-5% to provide the title compound as a tan oil (17.4 g, 87% yield).